In the rat, cholecystokinin (CCK) and dopamine (DA) coexist in a subpopulation of neurons of the ventral tegmental area (VTA) projecting to the nucleus accumbens. However, in the dorsal hippocampus, dopaminergic projections from the VTA do not contain CCK, the latter neurotransmitter being mainly localized in intrinsic hippocampal neurons. The present experiments were undertaken in order to compare the interactions of CCK and DA and the effects of lesioning VTA dopaminergic neurons in a region where these neurotransmitters coexist and in one where they do not. The effects of microiontophoretic applications of CCK, kainate (KA), glutamate (GLU) and DA were determined in control rats and in rats pretreated with a local injection of 6-hydroxydopamine (6-OHDA) in the VTA. In the nucleus accumbens and in the hippocampus of intact rats, DA exerted a similar depressant effect whether applied during CCK-, KA- or GLU-induced activations. The 6-OHDA lesion enhanced responsiveness of accumbens neurons to KA, GLU and CCK (the responsiveness to this latter peptide being increased by more than 15-fold) and the depressant effect of DA when applied during neuronal activation by KA or GLU but not when the same neurons were activated with CCK. In the dorsal hippocampus, the 6-OHDA lesion enhanced neuronal responsiveness to KA and DA in the CA1, but not in the CA3 region, whereas the responsiveness to CCK remained unchanged in both regions. These results suggest a physiological role for the coexistence of CCK and DA in the nucleus accumbens. The induction of a supersensitivity to DA in the CA1, but not in the CA3, region of the dorsal hippocampus following a VTA lesion is consistent with the regional distribution of the dopaminergic innervation in this structure.